4 DISCUSSION
During the 2018/2019 influenza season in Japan, baloxavir was prescribed
for 43% of children aged 7–15 years receiving antiviral treatment for
influenza. In comparison with NAIs, baloxavir prescription was not
associated with an increase in resource utilization within 9 days of
treatment, with the exception of the comparison with oseltamivir.
With respect to baloxavir use and clinical consequences among children,
data are limited to one published trial (including its secondary
analyses), a single-arm study without an active comparator drug, and
small case series reported from Japan [6,14, 19-22]. From a public
health standpoint, it remains unclear whether baloxavir use and virus
with reduced susceptibility to baloxavir would increase healthcare
resource use; this is why we designed our study to focus on healthcare
utilization rather than on the relationship between variant virus and
its downstream clinical outcomes in patients.
As compared with NAIs, baloxavir prescription was not overall associated
with increase in resource utilization within 9 days of treatment, except
in one subgroup analysis comparing with oseltamivir (aOR = 1.011;P <.001). In this subgroup analysis, we also found that
baloxavir reduced resource use relative to zanamivir (aOR = .995;P =.039). In these subgroup analyses, we did not perform P-value
adjustment for multiple comparisons for three reasons. First, although
sophisticated statistical approaches are proposed to account for
multiple comparisons, it is still controversial when and how the
adjustment for multiple comparisons should be done [23, 24]. Second,
statistical testing without scientifically sound hypothesis may result
in a false discovery that is difficult to explain biologically [24].
Our research hypothesis de novo was, due to less-susceptible
virus, baloxavir use might result in the increased healthcare use as
compared with all agents of NAI class, rather than a single NAI agent.
Third, our large-scale data could detect a small but statistically
significant difference that lacked clinical relevance [25].
Therefore, our subgroup analyses should be viewed as exploratory ones.
However, 1% of excess (or decrease) in healthcare resource use may be
substantial where baloxavir was prescribed for millions of patients in
one year, such as in Japan. Future researches are accordingly warranted
to assess whether our subgroup findings could be explained by chance
alone or not. Until then, it should be noted that the effect of
baloxavir was at best equivalent to that of oseltamivir [26].
In our study, oseltamivir accounted for about 15 % of antiviral
prescriptions for influenza, which proportion may be lower than in other
countries. There are two plausible reasons. First, Japan is the only
country to date that approved laninamivir for treatment of influenza.
This long-acting NAI with single-inhalation application is sometimes
preferred over a 5-days course of oseltamivir because of its convenience
[27]. Second reason is the concern for potential adverse event of
oseltamivir including neuropsychiatric symptoms among teenagers
[28], which negative association is currently considered unlikely
[17, 29]. Aside from the low frequency of oseltamivir prescription,
Japan is a top consumer of antivirals for influenza, which are commonly
prescribed even for children at low risk [27]. The prescription
pattern should be interpreted in this Japanese-specific context, but we
believe that this issue does not affect our primary analysis, that is,
the association between antiviral selection (ie, baloxavir vs NAIs) and
the subsequent medical resource use.
We did not integrate return visits to healthcare providers into the
primary composite outcome. In Japan, asymptomatic children recovering
from influenza often revisit physicians to affirm whether they can
return to school. Because this type of revisit could not be
differentiated in the claims record from a visit due to continuing
symptoms, return visits were only analyzed as one of the secondary
outcomes. In our data, revisits occurred in 47% of children, and this
event was independent of initial the antiviral class prescribed.
Similarly, death was not considered an outcome because influenza-related
death was expected to be infrequent among school-aged children.
This research describes the first-season experience of baloxavir use in
routine care setting involving pediatric patients at various risk levels
for severe influenza, which we believe to be the strength of our study.
This study also has limitations. First, our observation was based on a
single-year data with limited influenza B activity. Circulating strains
and the proportion of drug-resistant virus differ year by year, and the
further data are needed to ascertain whether our findings are
reproducible. Second, there were a number of unmeasured factors because
our data source was not constructed for research purposes; these
unmeasured factors included symptom duration, the interval between
symptom onset and drug use, the reason for selecting the antiviral drug
prescribed, vaccination status of each children (an out-of-pocket
service in Japan), and the indication of further medical resource use.
Our findings might therefore be subject to bias from these
effect-modifiers. Third, the generalizability of our research is unclear
to other age group or other counties with different healthcare system.
Fourth, whether patients adhered to the prescribed treatment is unknown.
Zanamivir requires a longer treatment course than baloxavir (5 days vs.
a single dose); hence, it is possible that the adherence rate was lower
in this group, and this difference may contribute to higher odds of
medical resource use in this group than in the baloxavir group. Finally,
the accuracy of the administrative claims record is uncertain or
debatable [30]. However, we believe that the exposure (defined by
prescription record) and outcomes (ie, resource utilization such as
hospitalization, tests and antibiotics use) were both recorded with high
accuracy because of the incentive for reimbursement by the healthcare
providers [31]. Further, comorbidities at high risk of severe
influenza were all independently associated with future resource
utilization, which may indicate that the impact of disease
misclassification was minimal, if it occurred at all.
In summary, as compared with NAIs, baloxavir prescription was not
overall associated with increases in healthcare resource utilization
within 9 days of treatment, except in one exploratory comparison with
oseltamivir. Future research efforts are warranted in broader clinical
contexts; these involve the following seasons, other regions outside
Japan, and the populations of different age group.